Irbesartan, might be 60 times more powerful to supress HBV entry than ezetimibe

A recent paper studied the effect of most FDA approved drugs on the inhibition of NTCP, the now known entry receptor for HBV. Ezetimibe was found to have a 50%inhibition conc of 25micromolar, while irbesartan, a commonly used angiotensin inhibitor to reduce blood pressure, was found to inhibit at 11.9 micromolar. Both compounds have similar MW, but irbesartan is given at up to 300mg per day, while exetimibe is dosed at 10mg. Thus the combination of 30fold higher approved dose and the double micromolar inhibition potency makes, in theory, irbesartan 60 fold more potent to inhibit Hbv entry. Of course, binding of these drugs to plasma proteins could cause substsntial differences in the available concentration on the hepatocyte membrane receptor, and the pharmacokinetics could further influence the in vivo efficscy. Tests in chimeric mice are urgently needed to determine the in vivo efficacy of this common, mostly beneficial medication on HBV reinfection inhibition.

Depending on activity of ongoing infected cell removal and the efficacy of entry inhibition of the myr dose actually used, the cccDNA pool will become progressively smaller with time as long as the patient will be on myr. Lesser infected cells means a reduced risk of HCC, but the overriding factor in HCC risk is the presence of cirrhosis and thev

Depending on activity of ongoing infected cell removal and the efficacy of entry inhibition of the myr dose actually used, the cccDNA pool will become progressively smaller with time as long as the patient will be on myr. Lesser infected cells means a reduced risk of HCC, but the overriding factor in HCC risk is the presence of cirrhosis and thev

Intensity of ongoing inflammation and oxidative stress. Unless myr is used all the way to hbsag seroconversion, stopping the treatment will restore the initial level of infected cells, of cccDNA and quant hbsag. Myr will cooperate with nucs in reinfection reduction, a combo with ifn will be even better.In all scenarios the myr dose will have to be very high for success.

Intensity of ongoing inflammation and oxidative stress. Unless myr is used all the way to hbsag seroconversion, stopping the treatment will restore the initial level of infected cells, of cccDNA and quant hbsag. Myr will cooperate with nucs in reinfection reduction, a combo with ifn will be even better.In all scenarios the myr dose will have to be very high for success.

Level of infected cell clearing that will lead to a zero net change. A decrease in reinfection by entry inhibition will therefore initially lead to a reduction of the total number of infected cells, but the lesser the infected cells remaining the slower the removal rate will be until it restabilizes on a lower level. Of course, if the reinfection rate is extremely low, then the removal will progress to such a substantial reduction in cccDNA, that the hbsag production shrinks to a critical threshold upon which its inhibition on immune clearance by s ag specific tells will be very low and a new force of cccDNA removal will slowly initiate, possibly leading to hbsag seroconversion.

If entry inhibition is stopped to early, the infection will spread again until it is matched by the removal rate.

Level of infected cell clearing that will lead to a zero net change. A decrease in reinfection by entry inhibition will therefore initially lead to a reduction of the total number of infected cells, but the lesser the infected cells remaining the slower the removal rate will be until it restabilizes on a lower level. Of course, if the reinfection rate is extremely low, then the removal will progress to such a substantial reduction in cccDNA, that the hbsag production shrinks to a critical threshold upon which its inhibition on immune clearance by s ag specific tells will be very low and a new force of cccDNA removal will slowly initiate, possibly leading to hbsag seroconversion.

If entry inhibition is stopped to early, the infection will spread again until it is matched by the removal rate.

1. "..Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.."
Q. Initial HBsAg conversion = When HBsAg becomes undetectable for the first time with use of R+Inf+M? Or..?

2. The news from Arrowhead (AH) says they claim 90% "Antigens" loss in their trial (with a Chimp). (I could not make out whether that was the surface antigen or e-antigen).
Q. Could we in any way compare/correlate the above with the figure you gave of 10% long term svr with AH? Similarly, the only 6% you gave for Irb despite it being possibly 60 times more powerful to suppress hbv than Eztmb (which itself showed promising results- i read Stef's update about that a few days back).

I am sure that with my limited knowledge, I am missing something very basic here.

Lastly, in general, is all the current research/progress reason enough to believe we are getting closer to subjugate this amazingly tough virus?

1. "..Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.."
Q. Initial HBsAg conversion = When HBsAg becomes undetectable for the first time with use of R+Inf+M? Or..?

2. The news from Arrowhead (AH) says they claim 90% "Antigens" loss in their trial (with a Chimp). (I could not make out whether that was the surface antigen or e-antigen).
Q. Could we in any way compare/correlate the above with the figure you gave of 10% long term svr with AH? Similarly, the only 6% you gave for Irb despite it being possibly 60 times more powerful to suppress hbv than Eztmb (which itself showed promising results- i read Stef's update about that a few days back).

I am sure that with my limited knowledge, I am missing something very basic here.

Lastly, in general, is all the current research/progress reason enough to believe we are getting closer to subjugate this amazingly tough virus?

Just an answer for your first question.
Through 29 days after initial treatment, maximal knock down of HBV DNA, e-antigen, and s-antigen were approximately 95%, 90%, and 90%, respectively..from Arrowhead website.
The second question can only be answered by Studyforhope as i am not clear on the figures myself

Just an answer for your first question.
Through 29 days after initial treatment, maximal knock down of HBV DNA, e-antigen, and s-antigen were approximately 95%, 90%, and 90%, respectively..from Arrowhead website.
The second question can only be answered by Studyforhope as i am not clear on the figures myself

Thanks.
Thats what I read myself. And I thought these figures do not seem to agree with what I deciphered from studyforhope's reply to my original question. I am sure he can further enlighten us on the subject.

Thanks.
Thats what I read myself. And I thought these figures do not seem to agree with what I deciphered from studyforhope's reply to my original question. I am sure he can further enlighten us on the subject.

And the removal rate depends on the immune respons, right? The less the number of infected the less the immûne respons , that is why we need interferon add on?

That reduction of the vigor of immune mediated clearance against a dwindling number of infected cells remaining is indeed a major problem in achieving lasting hbsag seroconversion or stable svr. That's why even after initial seroconversion and DNA undetectability and with a low but positive antibody level 75% of the primary svrs in the first replicor trial lost their seroconversion later.

Since a few infected cells will always remain, there is an absolute need for a maintenance immune function to control the remnants from spreading again.
It must be understood that even a good anti surface AB level is not able to prevent a slow spreading from remnant infected cells. This is caused by the limited speed of the immune complexing reaction, that will coat exiting virions with neutralizing antibodies. But an exiting virion needs to travel only a few microns to reach a neighboring uninflected hepatocyte, only a very high AB level can catch it in this localized scenario. Thus the infection will spread very slowly in local clusters.

This slowly growing cluster needs to be detected by a patrolling CTL, ready and activated enough to produce a high intensity gamma interferon burst, that will clear the cccDNA from this cluster.

Thus, yes in summary, that's why the add on interferon is needed even with replicor , to keep the immune vigor going once the stimulus has gotten very low.

And the removal rate depends on the immune respons, right? The less the number of infected the less the immûne respons , that is why we need interferon add on?

That reduction of the vigor of immune mediated clearance against a dwindling number of infected cells remaining is indeed a major problem in achieving lasting hbsag seroconversion or stable svr. That's why even after initial seroconversion and DNA undetectability and with a low but positive antibody level 75% of the primary svrs in the first replicor trial lost their seroconversion later.

Since a few infected cells will always remain, there is an absolute need for a maintenance immune function to control the remnants from spreading again.
It must be understood that even a good anti surface AB level is not able to prevent a slow spreading from remnant infected cells. This is caused by the limited speed of the immune complexing reaction, that will coat exiting virions with neutralizing antibodies. But an exiting virion needs to travel only a few microns to reach a neighboring uninflected hepatocyte, only a very high AB level can catch it in this localized scenario. Thus the infection will spread very slowly in local clusters.

This slowly growing cluster needs to be detected by a patrolling CTL, ready and activated enough to produce a high intensity gamma interferon burst, that will clear the cccDNA from this cluster.

Thus, yes in summary, that's why the add on interferon is needed even with replicor , to keep the immune vigor going once the stimulus has gotten very low.

1. "..Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.."
Q. Initial HBsAg conversion = When HBsAg becomes undetectable for the first time with use of R+Inf+M? Or..?

The disappearance of the surface antigen from the peripheral blood occurs after a few weeks of treatment with the replicor compound, but it is only the primary event that allows immune reconstitution and consequential infected cell clearance to the point, that several month later the true hbsag production even without artificial blockage is so low, hat it remains undetectable with most assays and a positive AB level can be detected at this point. This is the definition of initial hbsag conversion in the above context.

But this status is not truly stable in most patients, since a slow regrowth of the infection still occurs. Externally supported activation of immune surveillance is needed at this point, by ifn, therapeutic vaccines, thymosin alpha or by suppression of entry by effective doses of Myrcludex.

1. "..Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.."
Q. Initial HBsAg conversion = When HBsAg becomes undetectable for the first time with use of R+Inf+M? Or..?

The disappearance of the surface antigen from the peripheral blood occurs after a few weeks of treatment with the replicor compound, but it is only the primary event that allows immune reconstitution and consequential infected cell clearance to the point, that several month later the true hbsag production even without artificial blockage is so low, hat it remains undetectable with most assays and a positive AB level can be detected at this point. This is the definition of initial hbsag conversion in the above context.

But this status is not truly stable in most patients, since a slow regrowth of the infection still occurs. Externally supported activation of immune surveillance is needed at this point, by ifn, therapeutic vaccines, thymosin alpha or by suppression of entry by effective doses of Myrcludex.

2. The news from Arrowhead (AH) says they claim 90% "Antigens" loss in their trial (with a Chimp). (I could not make out whether that was the surface antigen or e-antigen).
Q. Could we in any way compare/correlate the above with the figure you gave of 10% long term svr with AH?

The available webcast lets you see the graph with the chimp data after two injections of the silencing rna mix. Look carefully at the numbers and consider how much hbsag is left after 90% is removed and what this reduction can possibly achieve. In case of the poor chimp, the remaining hbsag was 100000 units, in case of stefano or most of the people reporting their hbsag quant here it would be about 400 iu remaining. This is totally insufficient to unburden the immune system from the paralyzing effects of the surface antigen. If you dont keep injecting it will jump right back to the pretreatment values. The cccDNA or the infected cell number has not changed, it does not even need reinfection to recover to pretreatment values.

Nebertheless, since the polymerase and the core protein expression is likely also reduced, there is a small chance that, in combo with antivirals, the virion production is dramatically reduced to the extent that the reinfection rate becomes very low, allowing a downward shift in total infected cell and cccDNA numbers. If this progresses to the point that the hbsag output crosses the critical threshold...which is very, very low.. then a similar mechanism like with the replicor drug might occur. Provided that the intracellular shutdown of hbsag expression is not so intense as to prevent the processing of hbsag epitope fragments to the MHC pathway for presentation and tcell recognition on the surface of still infected hepatocytes. The combination of the effect estimation of all these mechanisms gives AH its rating towards helping true SVR, in combo with other approaches.

Arrowhead is BTW well aware of its limitations and thats why they call it a functional cure, meaning, that while you keep injecting the AH compounds like once pet month, the liver pathology will subside, since the immune attack will ease up. This is similar to what is achieved with the antivirals.

2. The news from Arrowhead (AH) says they claim 90% "Antigens" loss in their trial (with a Chimp). (I could not make out whether that was the surface antigen or e-antigen).
Q. Could we in any way compare/correlate the above with the figure you gave of 10% long term svr with AH?

The available webcast lets you see the graph with the chimp data after two injections of the silencing rna mix. Look carefully at the numbers and consider how much hbsag is left after 90% is removed and what this reduction can possibly achieve. In case of the poor chimp, the remaining hbsag was 100000 units, in case of stefano or most of the people reporting their hbsag quant here it would be about 400 iu remaining. This is totally insufficient to unburden the immune system from the paralyzing effects of the surface antigen. If you dont keep injecting it will jump right back to the pretreatment values. The cccDNA or the infected cell number has not changed, it does not even need reinfection to recover to pretreatment values.

Nebertheless, since the polymerase and the core protein expression is likely also reduced, there is a small chance that, in combo with antivirals, the virion production is dramatically reduced to the extent that the reinfection rate becomes very low, allowing a downward shift in total infected cell and cccDNA numbers. If this progresses to the point that the hbsag output crosses the critical threshold...which is very, very low.. then a similar mechanism like with the replicor drug might occur. Provided that the intracellular shutdown of hbsag expression is not so intense as to prevent the processing of hbsag epitope fragments to the MHC pathway for presentation and tcell recognition on the surface of still infected hepatocytes. The combination of the effect estimation of all these mechanisms gives AH its rating towards helping true SVR, in combo with other approaches.

Arrowhead is BTW well aware of its limitations and thats why they call it a functional cure, meaning, that while you keep injecting the AH compounds like once pet month, the liver pathology will subside, since the immune attack will ease up. This is similar to what is achieved with the antivirals.

The use of prepared anti hbsag antibodies ifrom high titer donors is commonly done to help to prevent reinfection after liver transplant and slso for newborns from infected mothers and after acute exposure. It is called HBIG .. Hepatitis b immune globuline.

It is very expensive and cannot be used in chronic hbv patients with any chance for a real effect since the amounts needed to neutralize the circulating hbsag levels are astronomical. For example to neutralize the daily production of a patient with 4000 iu about 100000 dollars worth of hbig per day would be needed, ongoingly. And dangerously high levels of immune complexes would be formed, damaging the kidneys.

HBIG was tried in the netherlands on patients with low hbsag, no real,effect, as expected.

A humanized monoclonal antibody named OSTAVIR against hbsag was tried in germany in cooperation with boehringer msnnheim. The trial was stopped because of a high rate of acute kidney damage.

A dual human monoclonal AB, invented and created by XTL in israel , named HEPEX B was advanced to a phase II human trial in chronic HBV patients in the usa. As expected, the suppression effect of super high doses in low hbsag patients was indeed achieved, but lasted just days after the treatment was stopped, with no real benefit to the patients.

HEPEX B was later sold to the us company CUBIST that tried to develop it for transplant reinfection prophylaxis. A phase II trial was sucessfully completed, but the FDA. requested over 400 transplant patients for the phase III trial, an impossible request that forced CUBIST to discontinue its development.

This is really sad, since HEPEX B exists, and could be used in combo with replicor or other approaches as a powerful entry inhibitor to prevent infection respreading in primary hbsag seroconverters that do not develop a high titer antibody.

The use of prepared anti hbsag antibodies ifrom high titer donors is commonly done to help to prevent reinfection after liver transplant and slso for newborns from infected mothers and after acute exposure. It is called HBIG .. Hepatitis b immune globuline.

It is very expensive and cannot be used in chronic hbv patients with any chance for a real effect since the amounts needed to neutralize the circulating hbsag levels are astronomical. For example to neutralize the daily production of a patient with 4000 iu about 100000 dollars worth of hbig per day would be needed, ongoingly. And dangerously high levels of immune complexes would be formed, damaging the kidneys.

HBIG was tried in the netherlands on patients with low hbsag, no real,effect, as expected.

A humanized monoclonal antibody named OSTAVIR against hbsag was tried in germany in cooperation with boehringer msnnheim. The trial was stopped because of a high rate of acute kidney damage.

A dual human monoclonal AB, invented and created by XTL in israel , named HEPEX B was advanced to a phase II human trial in chronic HBV patients in the usa. As expected, the suppression effect of super high doses in low hbsag patients was indeed achieved, but lasted just days after the treatment was stopped, with no real benefit to the patients.

HEPEX B was later sold to the us company CUBIST that tried to develop it for transplant reinfection prophylaxis. A phase II trial was sucessfully completed, but the FDA. requested over 400 transplant patients for the phase III trial, an impossible request that forced CUBIST to discontinue its development.

This is really sad, since HEPEX B exists, and could be used in combo with replicor or other approaches as a powerful entry inhibitor to prevent infection respreading in primary hbsag seroconverters that do not develop a high titer antibody.

if no big pharma buys replicor to continue its development in the big us and eu markets, then maybe a smaller approval scale in countries like the phillipines, bangladesch, etc is possible. That is exactly what Sciclone has done with thymosin alpha aka as zadaxin. It has approval in about 10 countries. Availability would unfortunately be limited to patients able to afford it by private payment.And one must never forget that it must be combined with strong immune enhancers like ifn or thymosin alpha to effect a truly stable seroconversion in the majority. But it remains by far the biggest step forward, because, for the large majority of patients, without very very high efficacy of surface antigen suppression, no permanent control of HBV seem possible, with the possible exception of ultra high entry inhibition combined with intense immune activation.

if no big pharma buys replicor to continue its development in the big us and eu markets, then maybe a smaller approval scale in countries like the phillipines, bangladesch, etc is possible. That is exactly what Sciclone has done with thymosin alpha aka as zadaxin. It has approval in about 10 countries. Availability would unfortunately be limited to patients able to afford it by private payment.And one must never forget that it must be combined with strong immune enhancers like ifn or thymosin alpha to effect a truly stable seroconversion in the majority. But it remains by far the biggest step forward, because, for the large majority of patients, without very very high efficacy of surface antigen suppression, no permanent control of HBV seem possible, with the possible exception of ultra high entry inhibition combined with intense immune activation.

updates on my results, i have got also previous hbsag tests done in pisa and the hbsag decrease was started from oct 2012 before trying ezetimibe and while on imiquimod suppository.
so the decrease was not an effect of ezetimibe.i d say no effect from ezetimibe both on bile acid and hbsag for now

effect from ibersartan:
no sides, beneficial effect on irritability present since started nucs in 2009 almost all gone, so in general feeling better, blood pressure normal.

very bad: frequent urination even hourly if i drink water, normal if i drink little water like 1-1.5liters per day

since my family has very low pressure genetically like 40/90 in the morning and 70-100 during the day without feeling abnormal i guess i can feel no difference on iberstartan or nucs increased my blood pressure during these last years

updates on my results, i have got also previous hbsag tests done in pisa and the hbsag decrease was started from oct 2012 before trying ezetimibe and while on imiquimod suppository.
so the decrease was not an effect of ezetimibe.i d say no effect from ezetimibe both on bile acid and hbsag for now

effect from ibersartan:
no sides, beneficial effect on irritability present since started nucs in 2009 almost all gone, so in general feeling better, blood pressure normal.

very bad: frequent urination even hourly if i drink water, normal if i drink little water like 1-1.5liters per day

since my family has very low pressure genetically like 40/90 in the morning and 70-100 during the day without feeling abnormal i guess i can feel no difference on iberstartan or nucs increased my blood pressure during these last years

discussing with pisa researchers they say etv+tdf is less potent than tdf mono because there might be competition among these drugs.so keeping the combo is beneficial only for resistance which is never seen on tdf mono but less potency and more sides

they suggest tdf mono and peginterferon add on when hbsag reaches 1000iu/ml.the hbvdna 31 iu/ml blip experienced in oct while trying tdf+etv+imiquimod suppository suggests me it is best keep the combo as long as no sides are experienced and that we really have no sufficent data to say tdf mono is superior to etv+tdf

discussing with pisa researchers they say etv+tdf is less potent than tdf mono because there might be competition among these drugs.so keeping the combo is beneficial only for resistance which is never seen on tdf mono but less potency and more sides

they suggest tdf mono and peginterferon add on when hbsag reaches 1000iu/ml.the hbvdna 31 iu/ml blip experienced in oct while trying tdf+etv+imiquimod suppository suggests me it is best keep the combo as long as no sides are experienced and that we really have no sufficent data to say tdf mono is superior to etv+tdf

the hbvdna monitoring is every 3 months and the detactable hbvdna at 31iu/ml was only in october (never happened while on the combo tdf+etv), i noted i had fever 38° from imiquimod the day of the test, so it may be just an occasional blip due to the imiquimod effects on immune system

the hbvdna monitoring is every 3 months and the detactable hbvdna at 31iu/ml was only in october (never happened while on the combo tdf+etv), i noted i had fever 38° from imiquimod the day of the test, so it may be just an occasional blip due to the imiquimod effects on immune system

Regarding blip of DNA positivity after imiquimod:
If there was a temporary increase in liver inflammation, it could reflect the temporary increased lysis of hepatocytes. The intracellular virions are by far more abundant than the ones released into the circulation and also, very importantly, the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading.
But you could have a temp release of intracellular virions by lysis, causing the blip.

The Pisa researchers are incorrect in saying that ENT plus TDF is less potent to suppress replication than TDF alone.
While it is fundamentally true, that the lack of synergism or even very effective additiveness among antivirals is caused by competing for access to the polymerase binding site like several cooks in a tiny kitchen, there is a slight measurable degree of additivity between TDF and ENT, when you have a clean and clear model situation to address that question.
I know of a research situation, where in a particular patient a successive exchange between TDF, then ENT, then TDF plus ENT was performed.
it was also repeated to confirm the findings. It was measured with a research only ultra high sensitive quant assay. The results were clear: TDF alone was slightly superior to ENT alone, and the combo was clearly superior over both monos, almost one log further reduction compared with the monos.

Technically the antivirals have different efficacy on the three block-able modes of the polymerase; Priming, reverse transcription and extension of the incomplete plus strand. ENT is the only one that effectively works on the priming step, but TDf is better in RT and single strand repair mechanisms inhibition.

Regarding blip of DNA positivity after imiquimod:
If there was a temporary increase in liver inflammation, it could reflect the temporary increased lysis of hepatocytes. The intracellular virions are by far more abundant than the ones released into the circulation and also, very importantly, the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading.
But you could have a temp release of intracellular virions by lysis, causing the blip.

The Pisa researchers are incorrect in saying that ENT plus TDF is less potent to suppress replication than TDF alone.
While it is fundamentally true, that the lack of synergism or even very effective additiveness among antivirals is caused by competing for access to the polymerase binding site like several cooks in a tiny kitchen, there is a slight measurable degree of additivity between TDF and ENT, when you have a clean and clear model situation to address that question.
I know of a research situation, where in a particular patient a successive exchange between TDF, then ENT, then TDF plus ENT was performed.
it was also repeated to confirm the findings. It was measured with a research only ultra high sensitive quant assay. The results were clear: TDF alone was slightly superior to ENT alone, and the combo was clearly superior over both monos, almost one log further reduction compared with the monos.

Technically the antivirals have different efficacy on the three block-able modes of the polymerase; Priming, reverse transcription and extension of the incomplete plus strand. ENT is the only one that effectively works on the priming step, but TDf is better in RT and single strand repair mechanisms inhibition.

So it looks like the ezetimibe was not realistically working on entry inhibition,
or more precisely to block the NTCP in a reliable 24 hours fashion. Your biliary acids were very low, which shows that there is no blockage of the HBV receptor. You have to consider the pharmacokinetics of the ezetimibe and possibly also the irbesartan. Blockage is only effective if it is a 24 hour continuous affair. If you leave the door open for the rats just one hour a day, your house will be filled with them.

to see if the irbesartan does a better job in vivo, you can simply measure your bile acids now after you take it. Considering the intense dynamic of the bile acid re-circulation ( 15 grams are recycled about 10 times per day!) any effect of blockage will be rapidly noticeable as an increase of circulating bile acids. That level might also change dynamically in response to various level of blockage of NTCP as the drug levels in blood will vary due to the drugs pharmacodynamic behaviour.
In other words, they might increase an hour after irbesartan, only to decrease to baseline 3 hours later. This needs to be considered in order not to interpret the values naively.

Under Myrcludex full blocking dose, the bile acids go up quite dramatically but its effect needs to be maintained 24 hours also, since obviously partial time entry inhibition is ineffective. Virions can wait in line until the doors open again, even if only shortly within 24 hours.

So it looks like the ezetimibe was not realistically working on entry inhibition,
or more precisely to block the NTCP in a reliable 24 hours fashion. Your biliary acids were very low, which shows that there is no blockage of the HBV receptor. You have to consider the pharmacokinetics of the ezetimibe and possibly also the irbesartan. Blockage is only effective if it is a 24 hour continuous affair. If you leave the door open for the rats just one hour a day, your house will be filled with them.

to see if the irbesartan does a better job in vivo, you can simply measure your bile acids now after you take it. Considering the intense dynamic of the bile acid re-circulation ( 15 grams are recycled about 10 times per day!) any effect of blockage will be rapidly noticeable as an increase of circulating bile acids. That level might also change dynamically in response to various level of blockage of NTCP as the drug levels in blood will vary due to the drugs pharmacodynamic behaviour.
In other words, they might increase an hour after irbesartan, only to decrease to baseline 3 hours later. This needs to be considered in order not to interpret the values naively.

Under Myrcludex full blocking dose, the bile acids go up quite dramatically but its effect needs to be maintained 24 hours also, since obviously partial time entry inhibition is ineffective. Virions can wait in line until the doors open again, even if only shortly within 24 hours.

"..the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading."

So do you agree with AASLD's practice guidelines for treatment criteria of hbe- Hep B? And the difference between chronic hbv and inactive hbv? (Or would you add/emphasize something else (tests like fibroscan, or even invasive ones like biopsy) in addition to the usual ALT, ultrasound and HBVDNA?).

"..the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading."

So do you agree with AASLD's practice guidelines for treatment criteria of hbe- Hep B? And the difference between chronic hbv and inactive hbv? (Or would you add/emphasize something else (tests like fibroscan, or even invasive ones like biopsy) in addition to the usual ALT, ultrasound and HBVDNA?).

The practice guidelines draw somewhat arbitrary lines to allow the practitioner to follow a programmed path and reduce responsibility in case there is a later bad development. I think that at Fibroscan or in certain cases even the addition of a biopsy helps to see the true status of the liver. The quant hbsag will help to decide whom to recommend for the ifn add on therapy and even more importantly to assess the response and likelihood early , so that unnecessary harmful ifn treatment can be early terminated.

The practice guidelines draw somewhat arbitrary lines to allow the practitioner to follow a programmed path and reduce responsibility in case there is a later bad development. I think that at Fibroscan or in certain cases even the addition of a biopsy helps to see the true status of the liver. The quant hbsag will help to decide whom to recommend for the ifn add on therapy and even more importantly to assess the response and likelihood early , so that unnecessary harmful ifn treatment can be early terminated.

If you can measure the bile acids under irbesartan treatment, it would be useful to measure them before taking the pill and then again two hours after,
If there is no increase after, then it means that the ntcp blockage is simply too weak in vivo even at max blood concentrations. If the bile acids are not elevated before the drug intake, then it would mean that the effect is not lasting long enough since the blood levels fall too quickly. Ideally they need to be above norm at both time points to hope for realistic HBV entry inhibition.

If you can measure the bile acids under irbesartan treatment, it would be useful to measure them before taking the pill and then again two hours after,
If there is no increase after, then it means that the ntcp blockage is simply too weak in vivo even at max blood concentrations. If the bile acids are not elevated before the drug intake, then it would mean that the effect is not lasting long enough since the blood levels fall too quickly. Ideally they need to be above norm at both time points to hope for realistic HBV entry inhibition.

«so that unnecessary harmful ifn treatment can be early terminated»
Why is interferon treatment harmfull? How bad is it harmfull? I think many people on interferon mono experience situation when there is no strong decline in hbs but DNA becomes undetectable. Statistics say if no decline in Hbs than stop interferon and switch to Nucs. The nucs goal is to make DNA undetectable. The question is – If hbv dna is already undetectable during the treatment by interferon and If interferon high cost is not an issue, what are the reasons for switching to NUCs rather then keeping interferon for 96 weeks? Are there any advantages of staying undetectable with interferon even no hbs decline (in short term, we all hope for hbs decline in long term post treatment) comparing to staying undetectable on NUCs?

«so that unnecessary harmful ifn treatment can be early terminated»
Why is interferon treatment harmfull? How bad is it harmfull? I think many people on interferon mono experience situation when there is no strong decline in hbs but DNA becomes undetectable. Statistics say if no decline in Hbs than stop interferon and switch to Nucs. The nucs goal is to make DNA undetectable. The question is – If hbv dna is already undetectable during the treatment by interferon and If interferon high cost is not an issue, what are the reasons for switching to NUCs rather then keeping interferon for 96 weeks? Are there any advantages of staying undetectable with interferon even no hbs decline (in short term, we all hope for hbs decline in long term post treatment) comparing to staying undetectable on NUCs?

i also like to menthion that on lampertico study with intf use for about 2 years there was one patient with no response for the first 48weeks who experienced the best response at 72 or 96weeks with the highest hbsab titer of the all patients in the trials....this is to say that sometimes you can t predict everything

i also like to menthion that on lampertico study with intf use for about 2 years there was one patient with no response for the first 48weeks who experienced the best response at 72 or 96weeks with the highest hbsab titer of the all patients in the trials....this is to say that sometimes you can t predict everything

If a patient becomes und on ifn mono then he should stay on ifn for at least a year, even if no drop in hbsag.
The reaction to ifn in terms of side effects is quite variable, many suffer from intense fatigue, feel like having a constant flu or become depressed, aggressive, even loose their jobs or marriages. If the sides are tolerable, then it should be given a chance to at least switch to a state of better immune control, even if hbsag loss cannot be achieved, which is currently the case in the majority of patients.
If there is any sign of autoimmune disorders, then the use of ifn can exercabate these, so there is a need to consider many variables.

If a patient becomes und on ifn mono then he should stay on ifn for at least a year, even if no drop in hbsag.
The reaction to ifn in terms of side effects is quite variable, many suffer from intense fatigue, feel like having a constant flu or become depressed, aggressive, even loose their jobs or marriages. If the sides are tolerable, then it should be given a chance to at least switch to a state of better immune control, even if hbsag loss cannot be achieved, which is currently the case in the majority of patients.
If there is any sign of autoimmune disorders, then the use of ifn can exercabate these, so there is a need to consider many variables.

April 08, 2013 12:05 PM Eastern Daylight Time
Transgene to Present New Data on TG1050 and TG4040 to Treat Chronic Hepatitis B and C at EASL 2013

STRASBOURG, France--(BUSINESS WIRE)--Regulatory News:

“TG4040 has recently completed successful phase 2 trial in patients with CHC”
Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and infectious diseases, today announced that favourable pre-clinical and clinical data on two Transgene products – TG1050 and TG4040 to treat chronic hepatitis B (CHB) and chronic hepatitis C (CHC), respectively – will be presented in oral presentations at this year’s European Association for the Study of the Liver (EASL) Conference (Amsterdam, Netherlands, April 24-28, 2013). The full abstracts are available at http://www.easl.eu.

“We are delighted to have the opportunity to present data at EASL, Europe’s largest liver conference. TG1050 is a novel immunotherapeutic to treat CHB that has shown very promising preclinical results and will soon be moving to early clinical development” stated Philippe Archinard, Chairman and CEO of Transgene. He added: “In addition to the preclinical proof-of-concept data published in September 20121, we have today released supplementary information, obtained in pre-clinical naïve and HBV murine models, on the immunogenicity of TG1050 and its capacity to induce long-term T cell response. This evidence further underlines our belief in the product’s potential to become an important new first in class immunotherapeutic to treat CHB, an area of unmet medical need.”

April 08, 2013 12:05 PM Eastern Daylight Time
Transgene to Present New Data on TG1050 and TG4040 to Treat Chronic Hepatitis B and C at EASL 2013

STRASBOURG, France--(BUSINESS WIRE)--Regulatory News:

“TG4040 has recently completed successful phase 2 trial in patients with CHC”
Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and infectious diseases, today announced that favourable pre-clinical and clinical data on two Transgene products – TG1050 and TG4040 to treat chronic hepatitis B (CHB) and chronic hepatitis C (CHC), respectively – will be presented in oral presentations at this year’s European Association for the Study of the Liver (EASL) Conference (Amsterdam, Netherlands, April 24-28, 2013). The full abstracts are available at http://www.easl.eu.

“We are delighted to have the opportunity to present data at EASL, Europe’s largest liver conference. TG1050 is a novel immunotherapeutic to treat CHB that has shown very promising preclinical results and will soon be moving to early clinical development” stated Philippe Archinard, Chairman and CEO of Transgene. He added: “In addition to the preclinical proof-of-concept data published in September 20121, we have today released supplementary information, obtained in pre-clinical naïve and HBV murine models, on the immunogenicity of TG1050 and its capacity to induce long-term T cell response. This evidence further underlines our belief in the product’s potential to become an important new first in class immunotherapeutic to treat CHB, an area of unmet medical need.”

Can you please share your opinion regarding stem cell treatment for chronic liver diseases? I have read a lot regarding this type of treatment and a lot emphasize that it will become the mainstream in the near future for liver disease mainly for ESLD which is curable only by liver transplant. Thank you in advance.

Can you please share your opinion regarding stem cell treatment for chronic liver diseases? I have read a lot regarding this type of treatment and a lot emphasize that it will become the mainstream in the near future for liver disease mainly for ESLD which is curable only by liver transplant. Thank you in advance.

As long as you have your own liver cells regenerating themselves there is no need or use for stem cells. Once the majority of these will have died and somehow their capacity to regenerate is exhausted , this type of treatment will make more sense, like in ESLD.
But the problem remains, that in the severely fibrotic and cirrhotic liver, there is also so much collagen, that the establishment of a meaningful liver micro-architecture is exceedingly difficult.

As long as you have your own liver cells regenerating themselves there is no need or use for stem cells. Once the majority of these will have died and somehow their capacity to regenerate is exhausted , this type of treatment will make more sense, like in ESLD.
But the problem remains, that in the severely fibrotic and cirrhotic liver, there is also so much collagen, that the establishment of a meaningful liver micro-architecture is exceedingly difficult.

people, we should be more focused where do they apply all this to real life cases.

For those of you that are doing research all this is very interesting sit and discuss things.. But we actually live with this nightmare. I am more interested in access to clinics where they apply all this. I will be the mice if it has to be.

The way I see things if things are known to work and not kill right away lets try it. That is what they should be doing.

people, we should be more focused where do they apply all this to real life cases.

For those of you that are doing research all this is very interesting sit and discuss things.. But we actually live with this nightmare. I am more interested in access to clinics where they apply all this. I will be the mice if it has to be.

The way I see things if things are known to work and not kill right away lets try it. That is what they should be doing.

normal range less than 6 micromol/l.drugs taken about 20hrs before test

i havent tested bile acids 2hrs after taking the pills, do you think it worths testing since it seems no ntcp block has happened?does it worth to try these drugs with peginterferon from other members to see if any boosting effect happens under that combo?

irbersatan is starting to be too heavy, extreme tireness especially at wake up has become not tollerable now, i can t get up before 10-11am

normal range less than 6 micromol/l.drugs taken about 20hrs before test

i havent tested bile acids 2hrs after taking the pills, do you think it worths testing since it seems no ntcp block has happened?does it worth to try these drugs with peginterferon from other members to see if any boosting effect happens under that combo?

irbersatan is starting to be too heavy, extreme tireness especially at wake up has become not tollerable now, i can t get up before 10-11am

yes, this is bad news, if the bile acids are not up, then the ntcp is not blocked. It might well be that the blood concentration of irbesartan falls to rapidly, then the blockage will disappear. Unfortunately, unless the blockage is consistent all 24 hours, it will allow reinfection. You could measure the bile acids 2 hours after drug intake, but even if it will increase it does not matter unless the effect lasts. The blockage of ntcp by myrcludex works so efficiently, that the bile acids are between 50 and 100 micromolar all the time, sometimes even higher after meals.

A combo with ifn is not going to increase the entry blocking effect, except of course that the further drop in produced virions will reduce the amount of visions seeking entry, but those will still be plenty enough. IFN will have another effect, however also limited, it will lead to destruction of a good percentage of virions whose core has entered the cytoplasm and prevent establishment of cccDNA in these cells, reducing the overall infection rate. But again, it will not be enough.

yes, this is bad news, if the bile acids are not up, then the ntcp is not blocked. It might well be that the blood concentration of irbesartan falls to rapidly, then the blockage will disappear. Unfortunately, unless the blockage is consistent all 24 hours, it will allow reinfection. You could measure the bile acids 2 hours after drug intake, but even if it will increase it does not matter unless the effect lasts. The blockage of ntcp by myrcludex works so efficiently, that the bile acids are between 50 and 100 micromolar all the time, sometimes even higher after meals.

A combo with ifn is not going to increase the entry blocking effect, except of course that the further drop in produced virions will reduce the amount of visions seeking entry, but those will still be plenty enough. IFN will have another effect, however also limited, it will lead to destruction of a good percentage of virions whose core has entered the cytoplasm and prevent establishment of cccDNA in these cells, reducing the overall infection rate. But again, it will not be enough.

if you have a regular meal with some fat or oil or egg in it, then the bile will flow. This will secrete between 5 to 10 grams of bile acids into your jejunum, which will be reabsorbed almost completely in your ileum in one to two hours.
Blood and extracellular space will hold only about 0.5grams at 50micromolar of bile acids. All that means, that if NTCP is blocked efficiently, the bile acids will rise strongly after 2 hours post cenam. If you take the drugs at the same time as the food, a clear increase in bile acids should occur if the test is done 2 or 3 hours later. It should increase to 20 or even 50 micromolar, if an effective blockage of NTCP is present.

If you stop the drugs now, it might be advisable to take them also one day before the test.

I would like to mention, that there is a second paper on finding substances that can block NTCP, where a database of a million compounds was screened and a few were found that were more efficient than irbesartan. But the efficiency was only moderately higher and those were esoteric chemicals far from any clinical or medical use. Thus the hope, that small moleule drugs can be found that will effectively block HBV entry and that could replace myrcludex seem to have little chance at this time.

if you have a regular meal with some fat or oil or egg in it, then the bile will flow. This will secrete between 5 to 10 grams of bile acids into your jejunum, which will be reabsorbed almost completely in your ileum in one to two hours.
Blood and extracellular space will hold only about 0.5grams at 50micromolar of bile acids. All that means, that if NTCP is blocked efficiently, the bile acids will rise strongly after 2 hours post cenam. If you take the drugs at the same time as the food, a clear increase in bile acids should occur if the test is done 2 or 3 hours later. It should increase to 20 or even 50 micromolar, if an effective blockage of NTCP is present.

If you stop the drugs now, it might be advisable to take them also one day before the test.

I would like to mention, that there is a second paper on finding substances that can block NTCP, where a database of a million compounds was screened and a few were found that were more efficient than irbesartan. But the efficiency was only moderately higher and those were esoteric chemicals far from any clinical or medical use. Thus the hope, that small moleule drugs can be found that will effectively block HBV entry and that could replace myrcludex seem to have little chance at this time.

I receive this information from hepatara site that they have clear the 1a study and myrcludex b is in Phase II clinical trials. so is any one has idea about outcome of phase I clinical study results

Product: Myrcludex B, a peptide inhibiting the penetration of virus into the liver cells.

Therapeutic focus: Chronic viral hepatitis B (HBV); chronic hepatitis D (HDV). In the future, indications for use can be expanded: viral encephalitis and other forms of hepatitis, HIV.

Status: Phase II clinical trials.

Partner: MYR, GmbH (Germany)

Description: Myrcludex B is a novel drug candidate, being a linear 47-amino acid chemically synthesized peptide. So far it is the single representative of a novel class of anti-HBV molecules, called entry inhibitors. The postulated mechanism of antiviral action is the highly specific and highly stable binding to HBV receptors on the surface of hepatocytes, which misdirects HBV to an unproductive pathway and thereby prevents an infection of the cell. This unique mechanism of action offers the possibility to address the two most important medical needs, namely long-term HBV eradication as well as antiviral activity against hepatitis D virus (HDV).

Despite the availability of appropriate drugs, there is still a number of unresolved medical problems concerning the treatment of hepatitis B, namely, how to achieve long-term eradication of the virus and how to prevent drug resistance. In view of the above it is essential to develop new therapies aimed at the still untouched stages of viral replication, such as the stage of the virus into hepatocytes.
In addition a similar mechanism of action provides the opportunity to prevent the development of delta hepatitis (hepatitis D).

In a series of preclinical studies Myrcludex B showed good safety and the ability to completely block the development of infection HBV. Phase Ia clinical trial showed the safety and good toleration of Myrcludex B in humans.

I receive this information from hepatara site that they have clear the 1a study and myrcludex b is in Phase II clinical trials. so is any one has idea about outcome of phase I clinical study results

Product: Myrcludex B, a peptide inhibiting the penetration of virus into the liver cells.

Therapeutic focus: Chronic viral hepatitis B (HBV); chronic hepatitis D (HDV). In the future, indications for use can be expanded: viral encephalitis and other forms of hepatitis, HIV.

Status: Phase II clinical trials.

Partner: MYR, GmbH (Germany)

Description: Myrcludex B is a novel drug candidate, being a linear 47-amino acid chemically synthesized peptide. So far it is the single representative of a novel class of anti-HBV molecules, called entry inhibitors. The postulated mechanism of antiviral action is the highly specific and highly stable binding to HBV receptors on the surface of hepatocytes, which misdirects HBV to an unproductive pathway and thereby prevents an infection of the cell. This unique mechanism of action offers the possibility to address the two most important medical needs, namely long-term HBV eradication as well as antiviral activity against hepatitis D virus (HDV).

Despite the availability of appropriate drugs, there is still a number of unresolved medical problems concerning the treatment of hepatitis B, namely, how to achieve long-term eradication of the virus and how to prevent drug resistance. In view of the above it is essential to develop new therapies aimed at the still untouched stages of viral replication, such as the stage of the virus into hepatocytes.
In addition a similar mechanism of action provides the opportunity to prevent the development of delta hepatitis (hepatitis D).

In a series of preclinical studies Myrcludex B showed good safety and the ability to completely block the development of infection HBV. Phase Ia clinical trial showed the safety and good toleration of Myrcludex B in humans.

can this irbesartan be taken with nucs, can we expect hbsag reduction with high base level, its possibility with interferon, its optimized doseing and possible side effects if any idea? may anybody summarise this whole disscussion.

can this irbesartan be taken with nucs, can we expect hbsag reduction with high base level, its possibility with interferon, its optimized doseing and possible side effects if any idea? may anybody summarise this whole disscussion.

i tried it with etv plus tdf plus ezetimibe plus ibersatan, it simply did not work, there has been no blocking on hepatocytes hbv receptors at least not enough to rise bile acids (which are a clear sign of potent hinibition of hbv receptors)

i tried it with etv plus tdf plus ezetimibe plus ibersatan, it simply did not work, there has been no blocking on hepatocytes hbv receptors at least not enough to rise bile acids (which are a clear sign of potent hinibition of hbv receptors)

Makes sense irbesartan helps against HBV. It is an ARB, and angiotensin 2 was found increased in hbv patients: http://www.ncbi.nlm.nih.gov/pubmed/1748416 ...too bad that members who already tried did not saw it working, maybe the concentration was not enough for the liver, who knows

But, maybe more important, irbesartan is a VDR agonist, meaning in the right concentration is able to activate the VDR by displacing all that stuff that blocks VDR (25d, bacteria, viruses, etc)...once the VDR is active, the cells can cure themselves

Makes sense irbesartan helps against HBV. It is an ARB, and angiotensin 2 was found increased in hbv patients: http://www.ncbi.nlm.nih.gov/pubmed/1748416 ...too bad that members who already tried did not saw it working, maybe the concentration was not enough for the liver, who knows

But, maybe more important, irbesartan is a VDR agonist, meaning in the right concentration is able to activate the VDR by displacing all that stuff that blocks VDR (25d, bacteria, viruses, etc)...once the VDR is active, the cells can cure themselves

Irbesartan, might be 60 times more powerful to supress HBV entry than ezetimibe

A recent paper studied the effect of most FDA approved drugs on the inhibition of NTCP, the now known entry receptor for HBV. Ezetimibe was found to have a 50%inhibition conc of 25micromolar, while irbesartan, a commonly used angiotensin inhibitor to reduce blood pressure, was found to inhibit at 11.9 micromolar. Both compounds have similar MW, but irbesartan is given at up to 300mg per day, while exetimibe is dosed at 10mg. Thus the combination of 30fold higher approved dose and the double micromolar inhibition potency makes, in theory, irbesartan 60 fold more potent to inhibit Hbv entry. Of course, binding of these drugs to plasma proteins could cause substsntial differences in the available concentration on the hepatocyte membrane receptor, and the pharmacokinetics could further influence the in vivo efficscy. Tests in chimeric mice are urgently needed to determine the in vivo efficacy of this common, mostly beneficial medication on HBV reinfection inhibition.

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